Profound changes in macronutrient composition of food have taken place since the agricultural revolution, leading to a higher dietary intake of carbohydrates at the expense of protein, and a dramatically increased intake of n-6 polyunsaturated fatty acids (PUFAs) at the expense of n-3 PUFAs. This review focuses on how macronutrients impact on molecular processes central to appetite regulation and energy homeostasis. We discuss the effects on transcription factors, implicated as key players in adipocyte differentiation and function, including PPARs, sterol regulatory element binding proteins and liver X receptors. Furthermore, as energy homeostasis is to a large extent orchestrated by the gut-brain axis, we discuss key hormones involved in the regulation of energy balance and appetite.